Browsing by Subject "UPDATE"

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  • Kaukonen, Maria; Quintero, Ileana B.; Mukarram, Abdul Kadir; Hytönen, Marjo K.; Holopainen, Saila; Wickström, Kaisa; Kyöstilä, Kaisa; Arumilli, Meharji; Jalomäki, Sari; Daub, Carsten O.; Kere, Juha; Lohi, Hannes; Consortium, the DoGA (2020)
    Author summary Retinitis pigmentosa (RP) is a blinding eye disease that affects nearly two million people worldwide. Several genes and variants have been associated with the disease, but still 30-80% of the patients lack genetic diagnosis. There is currently no standard treatment for RP, and much is expected from gene therapy. A similar disease, called progressive retinal atrophy (PRA), affects many dog breeds. We performed clinical, genetic and functional analyses to find the genetic cause for PRA in Miniature Schnauzers. We discovered two forms of PRA in the breed, named type 1 and 2, and show that they are genetically distinct as they map to different chromosomes, 15 and X, respectively. Further genetic, bioinformatic and functional analyses discovered a fully penetrant recessive variant in a putative silencer region for type 1 PRA. Silencer regions are important for gene regulation and we found that two of its predicted target genes, EDN2 and COL9A2, were overexpressed in the retina of the affected dog. Defects in both EDN2 and COL9A2 have been associated with retinal degeneration. This study provides new insights to retinal biology while the genetic test guides better breeding choices. Retinitis pigmentosa (RP) is the leading cause of blindness with nearly two million people affected worldwide. Many genes have been implicated in RP, yet in 30-80% of the RP patients the genetic cause remains unknown. A similar phenotype, progressive retinal atrophy (PRA), affects many dog breeds including the Miniature Schnauzer. We performed clinical, genetic and functional experiments to identify the genetic cause of PRA in the breed. The age of onset and pattern of disease progression suggested that at least two forms of PRA, types 1 and 2 respectively, affect the breed, which was confirmed by genome-wide association study that implicated two distinct genomic loci in chromosomes 15 and X, respectively. Whole-genome sequencing revealed a fully segregating recessive regulatory variant in type 1 PRA. The associated variant has a very recent origin based on haplotype analysis and lies within a regulatory site with the predicted binding site of HAND1::TCF3 transcription factor complex. Luciferase assays suggested that mutated regulatory sequence increases expression. Case-control retinal expression comparison of six best HAND1::TCF3 target genes were analyzed with quantitative reverse-transcriptase PCR assay and indicated overexpression of EDN2 and COL9A2 in the affected retina. Defects in both EDN2 and COL9A2 have been previously associated with retinal degeneration. In summary, our study describes two genetically different forms of PRA and identifies a fully penetrant variant in type 1 form with a possible regulatory effect. This would be among the first reports of a regulatory variant in retinal degeneration in any species, and establishes a new spontaneous dog model to improve our understanding of retinal biology and gene regulation while the affected breed will benefit from a reliable genetic testing.
  • Barylski, Jacub; Enault, François; Dutilh, Bas E.; Schuller, Margo B.P.; Edwards, Robert A.; Gillis, Annika; Klumpp, Jochen; Knezevic, Petar; Krupovic, Mart; Kuhn, Jens H.; Lavigne, Rob; Oksanen, Hanna M; Sullivan, Matthew B.; Jang, Ho Bin; Simmonds, Peter; Aiewsakun, Pakorn; Wittmann, Johannes; Tolstoy, Igor; Brister, J. Rodney; Kropinki, Andrew; Adriaenssens, Evelien M. (2020)
    Tailed bacteriophages are the most abundant and diverse viruses in the world, with genome sizes ranging from 10 kbp to over 500 kbp. Yet, due to historical reasons, all this diversity is confined to a single virus order-Caudovirales, composed of just four families: Myoviridae, Siphoviridae, Podoviridae, and the newly created Ackermannviridae family. In recent years, this morphology-based classification scheme has started to crumble under the constant flood of phage sequences, revealing that tailed phages are even more genetically diverse than once thought. This prompted us, the Bacterial and Archaeal Viruses Subcommittee of the International Committee on Taxonomy of Viruses (ICTV), to consider overall reorganization of phage taxonomy. In this study, we used a wide range of complementary methods-including comparative genomics, core genome analysis, and marker gene phylogenetics-to show that the group of Bacillus phage SPO1-related viruses previously classified into the Spounavirinae subfamily, is clearly distinct from other members of the family Myoviridae and its diversity deserves the rank of an autonomous family. Thus, we removed this group from the Myoviridae family and created the family Herelleviridae-a new taxon of the same rank. In the process of the taxon evaluation, we explored the feasibility of different demarcation criteria and critically evaluated the usefulness of our methods for phage classification. The convergence of results, drawing a consistent and comprehensive picture of a new family with associated subfamilies, regardless of method, demonstrates that the tools applied here are particularly useful in phage taxonomy. We are convinced that creation of this novel family is a crucial milestone toward much-needed reclassification in the Caudovirales order.
  • Bosnic-Anticevich, Sinthia; Costa, Elisio; Menditto, Enrica; Lourenco, Olga; Novellino, Ettore; Bialek, Slawomir; Briedis, Vitalis; Buonaiuto, Roland; Chrystyn, Henry; Cvetkovski, Biljana; Di Capua, Stefania; Kritikos, Vicky; Mair, Alpana; Orlando, Valentina; Paulino, Ema; Salimäki, Johanna; Söderlund, Rojin; Tan, Rachel; Williams, Dennis M.; Wroczynski, Piotr; Agache, Ioana; Ansotegui, Ignacio J.; Anto, Josep M.; Bedbrook, Anna; Bachert, Claus; Bewick, Mike; Bindslev-Jensen, Carsten; Brozek, Jan L.; Canonica, Giorgio Walter; Cardona, Victoria; Carr, Warner; Casale, Thomas B.; Chavannes, Niels H.; de Sousa, Jaime Correia; Cruz, Alvaro A.; Czarlewski, Wienczyslawa; De Carlo, Giuseppe; Demoly, Pascal; Devillier, Philippe; Dykewicz, Mark S.; Gaga, Mina; El-Gamal, Yehia; Fonseca, Joao; Fokkens, Wytske J.; Antonieta Guzman, Maria; Haahtela, Tari; Hellings, Peter W.; Illario, Maddalena; Carlos Ivancevich, Juan; Just, Jocelyne; Kaidashev, Igor; Khaitov, Musa; Khaltaev, Nikolai; Keil, Thomas; Klimek, Ludger; Kowalski, Marek L.; Kuna, Piotr; Kvedariene, Violeta; Larenas-Linnemann, Desiree E.; Laune, Daniel; Le, Lan T. T.; Carlsen, Karin C. Lodrup; Mahboub, Bassam; Maier, Dieter; Malva, Joao; Manning, Patrick J.; Morais-Almeida, Mario; Moesges, Ralph; Mullol, Joaquim; Munter, Lars; Murray, Ruth; Naclerio, Robert; Nannazova-Baranove, Leyla; Nekann, Kristof; Nyembue, Tshipukane Dieudonne; Okubo, Kimi; O'Hehir, Robyn E.; Ohta, Ken; Okamoto, Yoshitaka; Onorato, Gabrielle L.; Palkonen, Susanna; Panzner, Petr; Papadopoulos, Nikolaos G.; Park, Hae-Sim; Pawankar, Ruby; Pfaar, Oliver; Phillips, Jim; Plavec, Davor; Popov, Todor A.; Potter, Paul C.; Prokopakis, Emmanuel P.; Roller-Wirnsberger, Regina E.; Rottenn, Menachem; Ryan, Dermot; Sannolinski, Bolesfaw; Sanchez-Borges, Mario; Schunemann, Holger J.; Sheikh, Aziz; Sisul, Juan Carlos; Somekh, David; Stellato, Cristiana; To, Teresa; Todo-Bonn, Ana Maria; Tonnazic, Peter Valentin; Toppila-Salmi, Sanna; Valero, Antonio; Valiulis, Arunas; Valovirta, Errka; Ventura, Maria Teresa; Wagennnann, Martin; Wallace, Dana; Wasernnan, Susan; Wickman, Magnus; Yiallouros, Panayiotis K.; Yorgancioglu, Arzu; Yusuf, Osman M.; Zar, Heather J.; Zernotti, Mario E.; Zhang, Luo; Zidarn, Mihaela; Zuberbier, Torsten; Bousquet, Jean (2019)
    Pharmacists are trusted health care professionals. Many patients use over-the-counter (OTC) medications and are seen by pharmacists who are the initial point of contact for allergic rhinitis management in most countries. The role of pharmacists in integrated care pathways (ICPs) for allergic diseases is important. This paper builds on existing studies and provides tools intended to help pharmacists provide optimal advice/interventions/strategies to patients with rhinitis. The Allergic Rhinitis and its Impact on Asthma (ARIA)-pharmacy ICP includes a diagnostic questionnaire specifically focusing attention on key symptoms and markers of the disease, a systematic Diagnosis Guide (including differential diagnoses), and a simple flowchart with proposed treatment for rhinitis and asthma multimorbidity. Key prompts for referral within the ICP are included. The use of technology is critical to enhance the management of allergic rhinitis. However, the ARIA-pharmacy ICP should be adapted to local healthcare environments/situations as regional (national) differences exist in pharmacy care.
  • Lahti, Jouni; Laaksonen, Mikko; Lahelma, Eero; Rahkonen, Ossi (2011)
    BACKGROUND: Retirement is a major life change that is likely to affect lifestyles. The aim of this study was to examine changes in leisure-time physical activity of moderate and vigorous intensity among ageing employees facing transition to retirement over a follow-up of 5-7 years. METHODS: The baseline data were collected by questionnaire surveys in 2000-2002 among 40-60-year-old employees of the City of Helsinki. A follow-up survey was conducted among the baseline respondents in 2007 (n=7332, response rate 83%). Those who were on disability retirement at the follow-up were distinguished from old-age retirees. Leisure-time physical activity was measured using similar questions in both surveys. RESULTS: Old-age retirees increased significantly their time spent in moderate-intensity physical activity: women 31 minutes per week and men 42 minutes per week on average. Such changes were not found among disability retirees or those remaining employed. There were no changes in vigorous activity. Leisure-time physical inactivity at follow-up was lower among old-age retirees compared with employees of nearly the same age. Adjustments made for potential baseline covariates had no effects on these findings. CONCLUSIONS: Transition to old-age retirement was associated with an increase in moderate-intensity leisure-time physical activity and a decrease in the proportion of inactive. Encouraging people to leisure-time physical activity after retirement is worthwhile as the increase in free time brings new possibilities for it.
  • Pett, Helmi; Bradley, John; Okebe, Joseph; Dicko, Alassane; Tiono, Alfred B.; Goncalves, Bronner P.; Stone, Will; Chen, Ingrid; Lanke, Kjerstin; Neuvonen, Mikko; Mustaniemi, Anna-Liina; Eziefula, Alice C.; Gosling, Roly; D'Alessandro, Umberto; Drakeley, Chris; Niemi, Mikko; Bousema, Teun (2019)
    Single-dose primaquine (PQ) clears mature gametocytes and reduces the transmission of Plasmodium fakiparurn after artemisinin combination therapy. Genetic variation in CYP2D6, the gene producing the drug-metabolizing enzyme cytochrome P450 2D6 (CYP2D6), influences plasma concentrations of PQ and its metabolites and is associated with PQ treatment failure in Plasmodium vivax malaria. Using blood and saliva samples of varying quantity and quality from 8 clinical trials across Africa (n = 1,076), we were able to genotype CYP2D6 for 774 samples (72%). We determined whether genetic variation in CYP2D6 has implications for PQ efficacy in individuals with gametocytes at the time of PQ administration (n = 554) and for safety in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals treated with PQ (n = 110). Individuals with a genetically inferred CYP2D6 poor/intermediate metabolizer status had a higher gametocyte prevalence on day 7 or 10 after PQ than those with an extensive/ultrarapid CYP2D6 metabolizer status (odds ratio [OR] = 1.79 [95% confidence interval {CI}, 1.10, 2.90]; P = 0.018). The mean minimum hemoglobin concentrations during follow-up for G6PD-deficient individuals were 11.8 g/dl for CYP2D6 extensive/ultrarapid metabolizers and 12.1 g/dl for CYP2D6 poor/intermediate metabolizers (P = 0. 803). CYP2D6 genetically inferred metabolizer status was also not associated with anemia following PQ treatment (P = 0.331). We conclude that CYP2D6 poor/intermediate metabolizer status may be associated with prolonged gametocyte carriage after treatment with single-low-dose PQ but not with treatment safety.
  • Noguchi, Shuhei; Arakawa, Takahiro; Fukuda, Shiro; Furuno, Masaaki; Hasegawa, Akira; Hori, Fumi; Ishikawa-Kato, Sachi; Kaida, Kaoru; Kaiho, Ai; Kanamori-Katayama, Mutsumi; Kawashima, Tsugumi; Kojima, Miki; Kubosaki, Atsutaka; Manabe, Ri-ichiroh; Murata, Mitsuyoshi; Nagao-Sato, Sayaka; Nakazato, Kenichi; Ninomiya, Noriko; Nishiyori-Sueki, Hiromi; Noma, Shohei; Saijyo, Eri; Saka, Akiko; Sakai, Mizuho; Simon, Christophe; Suzuki, Naoko; Tagami, Michihira; Watanabe, Shoko; Yoshida, Shigehiro; Arner, Peter; Axton, Richard A.; Babina, Magda; Baillie, J. Kenneth; Barnett, Timothy C.; Beckhouse, Anthony G.; Blumenthal, Antje; Bodega, Beatrice; Bonetti, Alessandro; Briggs, James; Brombacher, Frank; Carlisle, Ailsa J.; Clevers, Hans C.; Davis, Carrie A.; Detmar, Michael; Dohi, Taeko; Edge, Albert S. B.; Edinger, Matthias; Ehrlund, Anna; Ekwall, Karl; Endoh, Mitsuhiro; Enomoto, Hideki; Eslami, Afsaneh; Fagiolini, Michela; Fairbairn, Lynsey; Farach-Carson, Mary C.; Faulkner, Geoffrey J.; Ferrai, Carmelo; Fisher, Malcolm E.; Forrester, Lesley M.; Fujita, Rie; Furusawa, Jun-ichi; Geijtenbeek, Teunis B.; Gingeras, Thomas; Goldowitz, Daniel; Guhl, Sven; Guler, Reto; Gustincich, Stefano; Ha, Thomas J.; Hamaguchi, Masahide; Hara, Mitsuko; Hasegawa, Yuki; Herlyn, Meenhard; Heutink, Peter; Hitchens, Kelly J.; Hume, David A.; Ikawa, Tomokatsu; Ishizu, Yuri; Kai, Chieko; Kawamoto, Hiroshi; Kawamura, Yuki I.; Kempfle, Judith S.; Kenna, Tony J.; Kere, Juha; Khachigian, Levon M.; Kitamura, Toshio; Klein, Sarah; Klinken, S. Peter; Knox, Alan J.; Kojima, Soichi; Koseki, Haruhiko; Koyasu, Shigeo; Lee, Weonju; Lennartsson, Andreas; Mackay-sim, Alan; Mejhert, Niklas; Mizuno, Yosuke; Morikawa, Hiromasa; Morimoto, Mitsuru; Moro, Kazuyo; Morris, Kelly J.; Motohashi, Hozumi; Mummery, Christine L.; Nakachi, Yutaka; Nakahara, Fumio; Nakamura, Toshiyuki; Nakamura, Yukio; Nozaki, Tadasuke; Ogishima, Soichi; Ohkura, Naganari; Ohno, Hiroshi; Ohshima, Mitsuhiro; Okada-Hatakeyama, Mariko; Okazaki, Yasushi; Orlando, Valerio; Ovchinnikov, Dmitry A.; Passier, Robert; Patrikakis, Margaret; Pombo, Ana; Pradhan-Bhatt, Swati; Qin, Xian-Yang; Rehli, Michael; Rizzu, Patrizia; Roy, Sugata; Sajantila, Antti; Sakaguchi, Shimon; Sato, Hiroki; Satoh, Hironori; Savvi, Suzana; Saxena, Alka; Schmidl, Christian; Schneider, Claudio; Schulze-Tanzil, Gundula G.; Schwegmann, Anita; Sheng, Guojun; Shin, Jay W.; Sugiyama, Daisuke; Sugiyama, Takaaki; Summers, Kim M.; Takahashi, Naoko; Takai, Jun; Tanaka, Hiroshi; Tatsukawa, Hideki; Tomoiu, Andru; Toyoda, Hiroo; van de Wetering, Marc; van den Berg, Linda M.; Verardo, Roberto; Vijayan, Dipti; Wells, Christine A.; Winteringham, Louise N.; Wolvetang, Ernst; Yamaguchi, Yoko; Yamamoto, Masayuki; Yanagi-Mizuochi, Chiyo; Yoneda, Misako; Yonekura, Yohei; Zhang, Peter G.; Zucchelli, Silvia; Abugessaisa, Imad; Arner, Erik; Harshbarger, Jayson; Kondo, Atsushi; Lassmann, Timo; Lizio, Marina; Sahin, Serkan; Sengstag, Thierry; Severin, Jessica; Shimoji, Hisashi; Suzuki, Masanori; Suzuki, Harukazu; Kawai, Jun; Kondo, Naoto; Itoh, Masayoshi; Daub, Carsten O.; Kasukawa, Takeya; Kawaji, Hideya; Carninci, Piero; Forrest, Alistair R. R.; Hayashizaki, Yoshihide (2017)
    In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of samples, consisting of a variety of primary cells, tissues, cell lines, and time series samples during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities.
  • Mauramo, Matti; Rohde, Luzius; Ramseier, Adrian M.; Rovo, Alicia; Waltimo, Tuomas (2017)
    The aetiology of hyposalivation in haematopoietic stem cell transplantation (HSCT) recipients is not fully understood. This study examined the effects of treatment-related aetiological factors, particularly medications, on stimulated salivary flow in HSCT recipients. Adult HSCT recipients (N = 118, 66 males, 27 autologous and 91 allogeneic transplants) were examined. Stimulated whole salivary flow rates (SWSFR) were measured before HSCT and at 6 and 12 months post-HSCT. Linear regression models were used to analyse the associations of medications and transplant-related factors with salivary flow rates, which were compared to salivary flow rates of generally healthy controls (N = 247). The SWSFR of recipients were lower pre-HSCT (mean +/- standard deviation, 0.88 +/- 0.56 ml/min; P <0.001), 6 months post-HSCT (0.84 +/- 0.61; P <0.001) and 12 months post-HSCT (1.08 +/- 0.67; P = 0.005) than the SWSFR of controls (1.31 +/- 0.65). In addition, hyposalivation (<0.7 ml/min) was more frequent among HSCT recipients pre-HSCT (P <0.001), 6 months post-HSCT (P <0.001) and 12 months post-HSCT (P = 0.01) than among controls. The SWSFR was observed to improve over time being significantly higher 12 months post-HSCT compared to pre-HSCT (P <0.001). The observed decrease of salivary flow could not be explained by the examined transplant-related factors and medications. Decreased stimulated salivary flow rates could not be explained by the examined factors alone; these findings indicate that hyposalivation in HSCT recipients exhibits a multifactorial aetiology. All HSCT recipients should be considered to be at high risk of hyposalivation and consequent oral diseases, and they should be treated accordingly.
  • Trotta, Luca; Hautala, Timo; Hamalainen, Sari; Syrjanen, Jaana; Viskari, Hanna; Almusa, Henrikki; Lepisto, Maija; Kaustio, Meri; Porkka, Kimmo; Palotie, Aarno; Seppanen, Mikko; Saarela, Janna (2016)
    Antibody class-switch recombination and somatic hypermutation critically depend on the function of activation-induced cytidine deaminase (AID). Rare variants in its gene AICDA have been reported to cause autosomal recessive AID deficiency (autosomal recessive hyper-IgM syndrome type 2 (HIGM2)). Exome sequencing of a multicase Finnish family with an HIGM2 phenotype identified a rare, homozygous, variant (c.416T > C, p.(Met139Thr)) in the AICDA gene, found to be significantly enriched in the Finnish population compared with other populations of European origin (38.56-fold, P <0.001). The population history of Finland, characterized by a restricted number of founders, isolation and several population bottlenecks, has caused enrichment of certain rare disease-causing variants and losses of others, as part of a phenomenon called the Finnish Disease Heritage. Accordingly, rare founder mutations cause the majority of observed Finnish cases in these mostly autosomal recessive disorders that consequently are more frequent in Finland than elsewhere. Screening of all currently known Finnish patients with an HIGM2 phenotype showed them to be homozygous for p.(Met139Thr). All the Finnish p.(Met139Thr) carriers with available data on their geographic descent originated from the eastern and northeastern parts of Finland. They were observed to share more of their genome identity by descent (IBD) than Finns in general (P <0.001), and they all carried a 207.5-kb ancestral haplotype containing the variant. In conclusion, the identified p.(Met139Thr) variant is significantly enriched in Finns and explains all thus far found AID deficiencies in Finland.
  • Gouya, Laurent; Ventura, Paolo; Balwani, Manisha; Bissell, D. Montgomery; Rees, David C.; Stölzel, Ulrich; Phillips, John D.; Kauppinen, Raili; Langendonk, Janneke G.; Desnick, Robert J.; Deybach, Jean-Charles; Bonkovsky, Herbert L.; Parker, Charles; Naik, Hetanshi; Badminton, Michael; Stein, Penelope E.; Minder, Elisabeth; Windyga, Jerzy; Bruha, Radan; Cappellini, Maria Domenica; Sardh, Eliane; Harper, Pauline; Sandberg, Sverre; Aarsand, Aasne K.; Andersen, Janice; Alegre, Félix; Ivanova, Aneta; Talbi, Neila; Chan, Amy; Querbes, William; Ko, John; Penz, Craig; Liu, Shangbin; Lin, Tim; Simon, Amy; Anderson, Karl E. (2020)
    Abstract Acute hepatic porphyria comprises a group of rare, genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months prior to the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a healthcare facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased healthcare utilization. Conclusions: Patients experienced attacks often requiring treatment in a healthcare facility and/or with hemin, as well as chronic symptoms that adversely influence day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies. This article is protected by copyright. All rights reserved.
  • Lahtinen, Perttu; Mattila, Eero; Anttila, Veli-Jukka; Tillonen, Jyrki; Teittinen, Matti; Nevalainen, Pasi; Salminen, Seppo; Satokari, Reetta; Arkkila, Perttu (2017)
    Fecal microbiota transplantation (FMT) is effective in recurrent Clostridium difficile infection (rCDI). Knowledge of the safety and efficacy of FMT treatment in immune deficient patients is scarce. FMT has been suggested as a potential method for an increasing number of new indications besides rCDI. Among our FMT-treated rCDI patients, we reviewed those with major comorbidities: two human immunodeficiency virus patients, six haemodialysis patients, two kidney transplant patients, two liver transplant patients and a patient with chronic lymphatic leukaemia. We also reviewed those treated with FMT for indications other than rCDI: Salmonella carriage (two patients), trimethylaminuria (two patients), small intestinal bacterial overgrowth (SIBO; one patient), and lymphocytic colitis (one patient), as well as a common variable immunodeficiency patient with chronic norovirus infection and ESBL-producing Escherichia coli (E. coli) carriage. Of the thirteen rCDI patients treated with FMT, eleven cleared the CDI. The observed adverse events were not directly attributable to FMT. Concerning the special indications, both Salmonellas and ESBL-producing E. coli were eradicated. One trimethylaminuria patient and one SIBO-patient reported a reduction of symptoms. Three patients did not experience a benefit from FMT: chronic norovirus, lymphocytic colitis and the other fish malodour syndrome. There were no reported side effects in this group. FMT appeared to be safe and effective for immunocompromised patients with rCDI. FMT showed promise for the eradication of antibiotic-resistant bacteria, but further research is warranted.
  • Global Sewage Surveillance; Hendriksen, Rene S.; Munk, Patrick; Njage, Patrick; Heikinheimo, Annamari; Berzins, Aivars (2019)
    Antimicrobial resistance (AMR) is a serious threat to global public health, but obtaining representative data on AMR for healthy human populations is difficult. Here, we use meta-genomic analysis of untreated sewage to characterize the bacterial resistome from 79 sites in 60 countries. We find systematic differences in abundance and diversity of AMR genes between Europe/North-America/Oceania and Africa/Asia/South-America. Antimicrobial use data and bacterial taxonomy only explains a minor part of the AMR variation that we observe. We find no evidence for cross-selection between antimicrobial classes, or for effect of air travel between sites. However, AMR gene abundance strongly correlates with socio-economic, health and environmental factors, which we use to predict AMR gene abundances in all countries in the world. Our findings suggest that global AMR gene diversity and abundance vary by region, and that improving sanitation and health could potentially limit the global burden of AMR. We propose metagenomic analysis of sewage as an ethically acceptable and economically feasible approach for continuous global surveillance and prediction of AMR.
  • Ekker, Merel S.; Jacob, Mina A.; van Dongen, Myrna M. E.; Aarnio, Karoliina; Annamalai, Arunkar K.; Arauz, Antonio; Arnold, Marcel; Barboza, Miguel A.; Bolognese, Manuel; Brouns, Raf; Chuluun, Batnairamdal; Chuluunbaatar, Enkhzaya; Dagvajantsan, Byambasuren; Debette, Stephanie; Don, Adi; Enzinger, Chris; Ekizoglu, Esme; Fandler-Hoefler, Simon; Fazekas, Franz; Fromm, Anette; Gattringer, Thomas; Gulli, Giosue; Hoffmann, Michael; Hora, Thiago F.; Jern, Christina; Jood, Katarina; Kamouchi, Masahiro; Kim, Young Seo; Kitazono, Takanari; Kittner, Steven J.; Kleinig, Timothy J.; Klijn, Catharina J. M.; Korv, Janika; Lee, Tsong-Hai; Leys, Didier; Maaijwee, Noortje A. M.; Martinez-Majander, Nicolas; Marto, Joao Pedro; Mehndiratta, Man M.; Mifsud, Victoria; Montanaro, Vinicius V.; Owolabi, Mayowa O.; Patel, Vinod B.; Phillips, Matthew C.; Piechowski-Iozwiak, Bartlomiej; Pikula, Aleksandra; Luis Ruiz-Sandoval, Jose; Sarnowski, Bettina; Schreuder, Floris H. B. M.; Swartz, Rick H.; Tan, K. S.; Tanne, David; Tatlisumak, T.; Thijs, Vincent; Tuladhar, Anil M.; Viana-Baptista, Miguel; Vibo, Riina; Wu, Teddy Y.; Yesilot, Nilufer; Waje-Andreassen, Ulrike; Pezzini, Alessandro; Putaala, Jukka; de Leeuw, Frank-Erik (2019)
    Introduction Worldwide, 2 million patients aged 18-50 years suffer a stroke each year, and this number is increasing. Knowledge about global distribution of risk factors and aetiologies, and information about prognosis and optimal secondary prevention in young stroke patients are limited. This limits evidence-based treatment and hampers the provision of appropriate information regarding the causes of stroke, risk factors and prognosis of young stroke patients. Methods and analysis The Global Outcome Assessment Life-long after stroke in young adults (GOAL) initiative aims to perform a global individual patient data meta-analysis with existing data from young stroke cohorts worldwide. All patients aged 18-50 years with ischaemic stroke or intracerebral haemorrhage will be included. Outcomes will be the distribution of stroke aetiology and (vascular) risk factors, functional outcome after stroke, risk of recurrent vascular events and death and finally the use of secondary prevention. Subgroup analyses will be made based on age, gender, aetiology, ethnicity and climate of residence.
  • Veromaa, Veera; Kautiainen, Hannu; Saxen, Ulla; Malmberg-Ceder, Kirsi; Bergman, Elina; Korhonen, Paeivi E. (2017)
    Aims: Ideal cardiovascular health has been defined by the American Heart Association as the absence of disease and the presence of seven key health factors and behaviours. However, little is known about the mental aspects associated with ideal cardiovascular health metrics. The objective of this study was to assess the relationships between psychosocial risk factors and ideal cardiovascular health metrics among Finnish women at municipal work units. Method: A cross-sectional study was conducted in Finland among 732 female employees (mean +/- SD age 48 +/- 10 years) from ten work units in 2014. Ideal cardiovascular health metrics were evaluated with a physical examination, laboratory tests, medical history and self-administrated questionnaires. Psychosocial risk factors (social isolation, stress, depressive symptoms, anxiety, hostility and type D personality) were assessed with core questions as suggested by the European Society of Cardiology. Results: The prevalence of having 5-7 ideal cardiovascular health metrics was 183 (25.0%), of whom 54.1% had at least one psychosocial risk factor. Anxiety (31.3%), work stress (30.7%) and type D personality (26.1%) were the most prevalent of the psychosocial risk factors. The prevalence of depressive symptoms (p
  • Makela, Mika J.; Gyllfors, Par; Valovirta, Erkka; Steffensen, Maria A.; Gronager, Pernille M.; Savolainen, Johannes; Winther, Lone (2018)
    Purpose: The SQ tree sublingual immunotherapy (SLIT)-tablet containing allergen extracts with the major allergen Bet v 1 from birch pollen is currently being developed for the treatment of tree pollen induced allergic rhinitis/conjunctivitis with or without asthma. The aim of this Phase II trial was to investigate the dose-related efficacy and safety of the SQ tree SLIT-tablet. Methods: This study was a randomized, parallel group, double-blind, placebo-controlled, multi-national trial conducted in Europe. A total of 637 participants were randomized equally to receive placebo or treatment with the SQ tree SLIT-tablet in doses of 0.5, 1, 2, 4, 7, or 12 development units (DU). Treatment was initiated 16 weeks before onset of the 2013 birch pollen season (BPS) and was continued throughout the BPS with a total duration of at least 6 months. During the BPS and tree pollen season (TPS), subjects assessed rhinoconjunctivitis symptoms and medication use on a daily basis in an electronic diary; weekly assessments of rhinoconjunctivitis quality of life were also made. Findings: Analysis of the average daily symptom score during the BPS and the TPS showed that the difference between active treatment and placebo was statistically significant for the 7 DU group (BPS, P = 0.02; TPS, P = 0.03), with no clear dose response relationship. All doses of the SQ tree SLIT-tablet induced changes from baseline in birch-specific IgE and IgG(4) that were statistically significant compared with placebo at all time points assessed (P <0.0001) with a clear dose-response relationship for birch specific IgG(4). In general, the SQ tree SLIT-tablet was well tolerated, with the majority of treatment-related adverse events (>= 95%) being mild or moderate in severity. The most frequently reported treatment related adverse events were generally related to the sublingual administration of the tablet (ie, they occurred in the oral cavity). (C) 2018 Elsevier HS Journals, Inc. All rights reserved.
  • Holmström, Ester; Efendijev, Ilmar; Raj, Rahul; Pekkarinen, Pirkka T.; Litonius, Erik; Skrifvars, Markus B. (2021)
    BackgroundCardiac arrest (CA) is a leading cause of death worldwide. As population ages, the need for research focusing on CA in elderly increases. This study investigated treatment intensity, 12-month neurological outcome, mortality and healthcare-associated costs for patients aged over 75 years treated for CA in an intensive care unit (ICU) of a tertiary hospital.MethodsThis single-centre retrospective study included adult CA patients treated in a Finnish tertiary hospital's ICU between 2005 and 2013. We stratified the study population into two age groups: 75 years. We compared interventions defined by the median daily therapeutic scoring system (TISS-76) between the age groups to find differences in treatment intensity. We calculated cost-effectiveness by dividing the total one-year healthcare-associated costs of all patients by the number of survivors with a favourable neurological outcome. Favourable outcome was defined as a cerebral performance category (CPC) of 1-2 at 12 months after cardiac arrest. Logistic regression analysis was used to identify independent associations between age group, mortality and neurological outcome.ResultsThis study included a total of 1,285 patients, of which 212 (16%) were >= 75 years of age. Treatment intensity was lower for the elderly compared to the younger group, with median TISS scores of 116 and 147, respectively (p
  • Sartelli, Massimo; Kluger, Yoram; Ansaloni, Luca; Coccolini, Federico; Baiocchi, Gian Luca; Hardcastle, Timothy C.; Moore, Ernest E.; May, Addison K.; Itani, Kamal M. F.; Fry, Donald E.; Boermeester, Marja A.; Guirao, Xavier; Napolitano, Lena; Sawyer, Robert G.; Rasa, Kemal; Abu-Zidan, Fikri M.; Adesunkanmi, Abdulrashid K.; Atanasov, Boyko; Augustin, Goran; Bala, Miklosh; Cainzos, Miguel A.; Chichom-Mefire, Alain; Cortese, Francesco; Damaskos, Dimitris; Delibegovic, Samir; Demetrashvili, Zaza; De Simone, Belinda; Duane, Therese M.; Ghnnam, Wagih; Gkiokas, George; Gomes, Carlos A.; Hecker, Andreas; Karamarkovic, Aleksandar; Kenig, Jakub; Khokha, Vladimir; Kong, Victor; Isik, Arda; Leppäniemi, Ari; Litvin, Andrey; Lostoridis, Eftychios; Machain, Gustavo M.; Marwah, Sanjay; McFarlane, Michael; Mesina, Cristian; Negoi, Ionut; Olaoye, Iyiade; Pintar, Tadeja; Pupelis, Guntars; Rems, Miran; Rubio-Perez, Ines; Sakakushev, Boris; Segovia-Lohse, Helmut; Siribumrungwong, Boonying; Talving, Peep; Ulrych, Jan; Vereczkei, Andras G.; Labricciosa, Francesco M.; Catena, Fausto (2018)
    Despite evidence supporting the effectiveness of best practices of infection prevention and management, many surgeons worldwide fail to implement them. Evidence-based practices tend to be underused in routine practice. Surgeons with knowledge in surgical infections should provide feedback to prescribers and integrate best practices among surgeons and implement changes within their team. Identifying a local opinion leader to serve as a champion within the surgical department may be important. The "surgeon champion" can integrate best clinical practices of infection prevention and management, drive behavior change in their colleagues, and interact with both infection control teams in promoting antimicrobial stewardship.
  • Greer, Mark; Berastegui, Cristina; Jaksch, Peter; Benden, Christian; Aubert, John; Roux, Antoine; Lhuillier, Elodie; Hirschi, Sandrine; Reynaud-Gaubert, Martine; Philit, Francois; Claustre, Johanna; LePalud, Pierre; Stern, Marc; Knoop, Christiane; Vos, Robin; Verschuuren, Erik; Fisher, Andrew; Riise, Gerdt; Hansson, Lennart; Iversen, Martin; Hämmäinen, Pekka; Wedel, Hans; Smits, Jacqueline; Gottlieb, Jens; Holm, Are M. (2018)
    Late-onset noninfectious pulmonary complications (LONIPCs) affect 6% of allogeneic stem cell transplantation (SCT) recipients within 5 years, conferring subsequent 5-year survival of 50%. Lung transplantation is rarely performed in this setting due to concomitant extrapulmonary morbidity, excessive immunosuppression and concerns about recurring malignancy being considered contraindications. This study assesses survival in highly selected patients undergoing lung transplantation for LONIPCs after SCT. SCT patients undergoing lung transplantation at 20 European centres between 1996 and 2014 were included. Clinical data pre- and post-lung transplantation were reviewed. Propensity score-matched controls were generated from the Eurotransplant and Scandiatransplant registries. Kaplan-Meier survival analysis and Cox proportional hazard regression models evaluating predictors of graft loss were performed. Graft survival at 1, 3 and 5 years of 84%, 72% and 67%, respectively, among the 105 SCT patients proved comparable to controls (p=0.75). Sepsis accounted for 15 out of 37 deaths (41%), with prior mechanical ventilation (HR 6.9, 95% CI 1.0-46.7; p Lung transplantation outcomes following SCT were comparable to other end-stage diseases. Lung transplantation should be considered feasible in selected candidates. No SCT-specific factors influencing outcome were identified within this carefully selected patient cohort.
  • van Uitert, Miranda; Moerland, Perry D.; Enquobahrie, Daniel A.; Laivuori, Hannele; van der Post, Joris A. M.; Ris-Stalpers, Carrie; Afink, Gijs B. (2015)
    Studies using the placental transcriptome to identify key molecules relevant for preeclampsia are hampered by a relatively small sample size. In addition, they use a variety of bioinformatics and statistical methods, making comparison of findings challenging. To generate a more robust preeclampsia gene expression signature, we performed a meta-analysis on the original data of 11 placenta RNA microarray experiments, representing 139 normotensive and 116 preeclamptic pregnancies. Microarray data were pre-processed and analyzed using standardized bioinformatics and statistical procedures and the effect sizes were combined using an inverse-variance random-effects model. Interactions between genes in the resulting gene expression signature were identified by pathway analysis (Ingenuity Pathway Analysis, Gene Set Enrichment Analysis, Graphite) and protein-protein associations (STRING). This approach has resulted in a comprehensive list of differentially expressed genes that led to a 388-gene meta-signature of preeclamptic placenta. Pathway analysis highlights the involvement of the previously identified hypoxia/HIF1A pathway in the establishment of the preeclamptic gene expression profile, while analysis of protein interaction networks indicates CREBBP/EP300 as a novel element central to the preeclamptic placental transcriptome. In addition, there is an apparent high incidence of preeclampsia in women carrying a child with a mutation in CREBBP/EP300 (Rubinstein-Taybi Syndrome). The 388-gene preeclampsia meta-signature offers a vital starting point for further studies into the relevance of these genes (in particular CREBBP/EP300) and their concomitant pathways as biomarkers or functional molecules in preeclampsia. This will result in a better understanding of the molecular basis of this disease and opens up the opportunity to develop rational therapies targeting the placental dysfunction causal to preeclampsia.
  • Marttila, Minttu; Mubashir, Hanif; Lemola, Elina; Nowak, Kristen J.; Laitila, Jenni; Gronholm, Mikaela; Wallgren-Pettersson, Carina; Pelin, Katarina (2014)
    Background: Nemaline myopathy (NM) is a rare genetic muscle disorder, but one of the most common among the congenital myopathies. NM is caused by mutations in at least nine genes: Nebulin (NEB), alpha-actin (ACTA1), alpha-tropomyosin (TPM3), beta-tropomyosin (TPM2), troponin T (TNNT1), cofilin-2 (CFL2), Kelch repeat and BTB (POZ) domain-containing 13 (KBTBD13), and Kelch-like family members 40 and 41 (KLHL40 and KLHL41). Nebulin is a giant (600 to 900 kDa) filamentous protein constituting part of the skeletal muscle thin filament. Around 90% of the primary structure of nebulin is composed of approximately 35-residue alpha-helical domains, which form super repeats that bind actin with high affinity. Each super repeat has been proposed to harbor one tropomyosin-binding site. Methods: We produced four wild-type (WT) nebulin super repeats (S9, S14, S18, and S22), 283 to 347 amino acids long, and five corresponding repeats with a patient mutation included: three missense mutations (p.Glu2431Lys, p.Ser6366Ile, and p.Thr7382Pro) and two in-frame deletions (p.Arg2478_Asp2512del and p.Val3924_Asn3929del). We performed F-actin and tropomyosin-binding experiments for the nebulin super repeats, using co-sedimentation and GST (glutathione-S-transferase) pull-down assays. We also used the GST pull-down assay to test the affinity of WT nebulin super repeats for WT alpha- and beta-tropomyosin, and for beta-tropomyosin with six patient mutations: p.Lys7del, p. Glu41Lys, p.Lys49del, p.Glu117Lys, p.Glu139del and p.Gln147Pro. Results: WT nebulin was shown to interact with actin and tropomyosin. Both the nebulin super repeats containing the p.Glu2431Lys mutation and nebulin super repeats lacking exon 55 (p.Arg2478_Asp2512del) showed weak affinity for F-actin compared with WT fragments. Super repeats containing the p.Ser6366Ile mutation showed strong affinity for actin. When tested for tropomyosin affinity, super repeats containing the p.Glu2431Lys mutation showed stronger binding than WT proteins to tropomyosin, and the super repeat containing the p.Thr7382Pro mutation showed weaker binding than WT proteins to tropomyosin. Super repeats containing the deletion p. Val3924_Asn3929del showed similar affinity for actin and tropomyosin as that seen with WT super repeats. Of the tropomyosin mutations, only p.Glu41Lys showed weaker affinity for nebulin (super repeat 18). Conclusions: We demonstrate for the first time the existence of direct tropomyosin-nebulin interactions in vitro, and show that nebulin interactions with actin and tropomyosin are altered by disease-causing mutations in nebulin and tropomyosin.